A Straightforward and Efficient Method for the Synthesis of Diversely Substituted β-Aminoketones and γ-Aminoalcohols from 3-(<i>N,N</i>-Dimethylamino)propiophenones as Starting Materials

Abonı́a, Rodrigo; Arteaga, Danny; Castillo, Juan C.; Insuasty, Braulio; Quiroga, Jairo; Ortíz, Alejandro

doi:10.5935/0103-5053.20130177

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“…In view of the above, we envisioned that our previous results on the synthesis of γ-aminoalcohols type 15 and 19 [ 18 , 19 ], could be exploited as alternative approaches for the synthesis of naftifine and analogues mediated by Mannich-type reactions. In this direction, two straightforward strategies, shown in Scheme 2 and Scheme 3 , were proposed.…”

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Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents

et al. 2018

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Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues 16 and 20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, the γ-aminoalcohols 15 and 19 were obtained as the key intermediates and their subsequent dehydration catalyzed either by Brønsted acids like H2SO4 and HCl or Lewis acid like AlCl3, respectively, led to naftifine, along with the target allylamines 16 and 20. The antifungal assay results showed that intermediates 18 (bearing both a β-aminoketo- and N-methyl functionalities in their structures) and products 20 were the most active. Particularly, structures 18b, 18c, and the allylamine 20c showed the lowest MIC values, in the 0.5–7.8 µg/mL range, against the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Interesting enough, compound 18b bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against Candida albicans and Cryptococcus neoformans with MIC80 = 7.8 µg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 µg/mL against C. neoformans.

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confidence: 99%

Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents

et al. 2018

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“…Once established the better reaction conditions and in order to determine its scope and general character, this approach was extended to the benzylamines chemset 19{1-3,8,22} and propiophenones chemset 29{1-4}, see Table 3. 55 Satisfactorily, the corresponding β-aminoketones 30{1,1} through 30{22,2} were fairly obtained in 62-90% isolated yields, as shown in the Table 3. Once the β-aminoketones 30 were efficiently obtained, we proceeded with the reduction process of the carbonyl groups, (i.e.…”

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“…Synthesis of novel β-aminoketones (30{6,1}, 30{6,2} and 30{23,4}) and γ-aminoalcohols (31{6,1} and 31{6,2}) from the reaction of propiophenones (29{1}, 29{2} and 29{4} with morpholine 19{6} and piperidine 19{23}, respectively. 55 To further confirm the practical scope of our two-step protocol, we used it to develop an alternative synthetic route towards Naftifine ® , a recognized and highly active antifungal agent. [60][61][62] Thus, following the synthetic sequence described in Scheme 12 Naftifine ® was satisfactorily obtained in 86% isolated yield.…”

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“…Proposed sequence for the synthesis of the novel β-aminoketones 30 and γ-aminoalcohols 31 from the benzylmethylamine derivatives 19 through a Mannich-type strategy. 55 To start with our purposes, as a model reaction, a mixture of benzylmethylamine 19{1} (R = Me) (1 mmol) and N,N-dimethylaminopropiophenone hydrochloride 29{1} (Ar = Ph) 56,57 (1 mmol) was subjected to different reaction conditions in order to obtain the β-aminoketone product 30{1,1} (i.e step (i), Scheme 10). The best result (88% yield of product 30{1,1}), was achieved when the starting materials were refluxed in a mixture 5:1 v/v of p-dioxane:TEA.…”

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“…The reduction process of ketones 30 was efficiently performed by two different approaches: (a) by a catalytic hydrogenation on a Parr apparatus in the presence of Nickel-Raney as catalyst, methanol as solvent at room temperature, 58,59 and (b) by a chemical reduction with NaBH 4 in methanol at room temperature to afford the expected γ-aminoalcohols 31 in (72-93%) or (57-96%) isolated yields, respectively, Table 3. 55 Table 3. Synthesis of the novel β-aminoketones 30{1,1} through 30{22,2} and γ-aminoalcohols 31{1,1} through 31{22,2} 55 a Values in parentheses correspond to the isolated yields of alcohols obtained by catalytic hydrogenation.…”

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Recent contributions to the Diversity-Oriented Synthesis (DOS) mediated by iminium ions through multicomponent Mannich-type reactions

Abonı́a¹,

Castillo²,

Kotali³

2017

Arkivoc

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This short account summarizes the most recent contributions of the author and his collaborators to the Diversity Oriented Synthesis (DOS) mediated, at least in a step of the process, by Mannich-type reactions (MTR) and using formaldehyde as common starting material in all cases. Through this strategy, diverse nitrogen-containing acyclic and heterocyclic systems were synthesized, whether in straightforward or multicomponent approaches.

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Manganese-Catalyzed Anti-Markovnikov Hydroamination of Allyl Alcohols via Hydrogen-Borrowing Catalysis

2021

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Controlling the selectivity in hydroamination reaction is an extremely challenging yet highly desirable task for the selective diversification of amines. In this manuscript, a selective formal anti-Markovnikov hydroamination of allyl alcohols is presented. It enables the versatile synthesis of valuable γ-amino alcohol building blocks. A phosphine-free Earth's abundant manganese(I) complex catalyzed the reaction under hydrogen borrowing conditions. A vast range of aliphatic, aromatic amines, drug molecules, and natural product derivatives underwent successful hydroamination with primary and secondary allylic alcohols with excellent functional group tolerance (57 examples). The catalysis could be performed on a gram scale and have been applied for the synthesis of drug molecules. The mechanistic studies revealed the metal-ligand bifunctionality as well as hemilability of the ligand backbone as the key design principle for the success of this catalysis. needed to be highly chemoselective for catalyzing anti-Markovnikov hydroamination reaction, avoiding competing reduction of C = X (X = C, N) bonds, 21 allylic substitution, 5s, 22 and allylic isomerization. 23 Scheme 1. a) Drug Molecules Prepared from γ-Amino Alcohols. b) Metal Catalyzed Homogeneous Anti-Markovnikov Hydroamination of Allyl Alcohol.sidearm to be the salient factors operating to the success of this waste-free hydrogen transfer catalysis. ASSOCIATED CONTENT Supporting InformationThe Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Experimental procedures, analytical data, kinetic data, NMR spectra of compounds and complexes.

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A Straightforward and Efficient Method for the Synthesis of Diversely Substituted β-Aminoketones and γ-Aminoalcohols from 3-(N,N-Dimethylamino)propiophenones as Starting Materials

Cited by 4 publications

References 0 publications

Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents

Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents

Recent contributions to the Diversity-Oriented Synthesis (DOS) mediated by iminium ions through multicomponent Mannich-type reactions

Manganese-Catalyzed Anti-Markovnikov Hydroamination of Allyl Alcohols via Hydrogen-Borrowing Catalysis

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